Measuring a concentration of a substance is a common technical task. This task is particular challenging, if the substance under investigation is contained in a mixture of different substances. Such a matrix requires a measurement principle not only of high sensitivity, but also of high selectivity to obtain a good measurement of concentration. Often, a single measurement is not sufficient and costly selection procedure, for instance gas chromatography etc., must be utilized. The difficulty of the measurement task increases with the complexity of the matrix.
Very complex substance mixtures are usually be found in biology. For this reason, measurement of a concentration of a substance in a biological matrix is one of the most challenging tasks.
Generally, there is a clear trade-off between the measurement complexity and the options to miniaturize a measurement system. However, miniaturized sensor systems are very attractive for biological applications. It is well known, that a well regulated concentration of certain substances such as glucose, sodium chloride, uric acid, amino acid, etc. is vital for humans. In case of a disease the biological regulation of the concentration can misalign and the concentration of one or more vital substances can be outside the physiologically harmless range. To avoid such disturbation through therapeutic treatment requires to know the current concentration of the substances under investigation; thus, the concentration must be measured, sometimes continuously. Single use test strips are not suitable, then.
For instance diabetes mellitus, caused by a disturbed regulation of the metabolism of glucose in the body, is causing too high (hyperglycenic) or too low (hypoglycenic) concentrations. In the long term, this causes irreversible dieback of nerve cells and a set of further diseases mainly of blood vessels. Resulting diseases can be blindness, loss of renal function, cardiac infarction, high blood pressure and the dieback of extremities. The therapy of diabetes requires an adjustment of the glucose level on a permanent base within the harmless medial range as precisely as possible, e. g. by administering insulin or glucose. Schedule and volume of insulin injections or the need to take food depend on the current glucose concentration as well as the concentration change during the day.
The concentration of glucose is, therefore, an example for a measurement task of a substance concentration in a complex matrix, which is to be monitored continuously without interruption and without extensive repetitive adjustments. All treatments and therapies today are based on influencing the blood glucose level. This is the reason why most glucose concentration measurement devices measure the glucose concentration in the blood. In is also known, to utilize the interstitial fluid, since its glucose content follows the concentration in blood with only a small time delay.
E.g. DE 19911265 C2 describes a device for measuring the concentration of glucose in protein-containing aqueous solutions, in particular in the interstitial tissue fluid, where a dialysis extract is characterized polarimetrically and spectroscopic at the same time. The parallel application of two measurement techniques causes a significant complexity and expenditure. The described solution results in an expected large technical construction. In addition a plasite dialysis membrane for the separation of substances is required, while the challenging technical coupling of this membrane to the optical measurement system is not described in detail.
A similar approach is described in DE 3736092 A1.
When measuring the concentration of the substance in a biological tissue, the tissue or the interstitial fluid forms a matrix. To address this issue, a sensor is required which can be inserted into the tissue to enable a permanent observation of the substance concentration. Such sensor is known from DE 102007031284 A1. This apparatus realizes measurement chamber, optical transmitter and receiver as a compact unit, which can be inserted into the body of a mammal.
To insert into the body of a mammal requires a reliable sterilization of the sensor. The apparatus of DE 102007031284 A1 requires also sterilization of the measuring fluid enclosed in the sensor. This can be done only by the application of ionizing (radioactive) radiation, which involves the issue of damage of the transmitter and of the receiver from the ionizing radiation.
Manufacturing the sensor according to DE 102007031284 A1 requires to fill of the measurement chamber without any bubbles, which requires the use of vacuum for ensuring process reliability. At the same time, this requires that the whole sensor is immersed within the measurement fluid. In such vacuum assisted filling one must take care that transmitter and receiver and in particular their optical components are not filled with the measurement fluid. This involves a significant effort to protect these elements.
The measurement chamber wall used in the sensor concept according to DE 102007031284 A1 allows diffusion for the measurement fluid or at least a part thereof. To avoid evaporation or leakage of the measurement fluid, this approach stores the sensor in a storage container topped up with the measurement fluid. In case of glucose measurement, the storage container is filled with saline solution which is the measurement fluid. Such storage results in demanding specifications and high manufacturing costs to protect optical and electronic components of the sensors. All electric connections and wiring need to be protected against corrosion caused by the saline solution. Storage in the storage container filled with saline solution imposes furthermore a large risk for the long term stability and heavily reduces for the maximum shelf life of the sensor.